The objectives of this ongoing proposed research are to make creative contributions to the synthesis of complex naturally occurring substances possessing clinically significant biological activity. This grant will continue to develop new stereoselective reactions and the application of this methodology to the asymmetric synthesis of complex polyketide antibiotics and antineoplastic agents. The synthesis targets will include amphinidinol 3, aflastatin 3, (+) peloruside A, salvinorin A, phorbol, and the tetracycline family of antibiotics. An important new approach in the synthesis of polycyclic structures from acyclic precursors has been illustrated in the design of salvinorin A, phorbol, and tetracycline. All of these syntheses begin with bond constructions that are stereochemically regulated by acyclic stereocontrol. The carbon framework is then assembled by a series of intramolecular, transannular processes from medium-ring macrocycles. Along with polynucleotides, peptides, and polysaccharides, polyketides represent the fourth broad family of naturally occurring materials that are assembled from common subunits. In extending the comparison with peptide synthesis, polyketide assembly through complex aldol bond constructions is a far greater challenge that the analogous peptide fragment assembly analogy since up to two new stereocenters are created during the fragment coupling event. Our long term objective in this grant has been the development of all of the methodology to assemble polyketide-derived natural products. This objective includes the development of chiral enolate methodology, the study of remote stereocenters on carbonyl and enolate pi-face selectivities, and the development of predictive models for double stereodifferentiating aldol addition reactions. The goal is to improve reaction design predictability. The polyketide targets are amphidinol A, aflastatin 3, peloruside, and salvinorin A. Chemical synthesis provides the capacity to produce chemotherapeutic agents, and chemical reactions are the irreplaceable tools of the medicinal chemist engaged in the drug discovery process. Advances in chemical reaction technology reduce the interval between the conception of the chemical entity as a potential drug candidate and its synthesis for subsequent biological evaluation. As a consequence, organic synthesis is a critical discipline that continues to have an important impact on the fields of both medicine and biology.